MYBPC3, encoding cardiac myosin-binding protein-C is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM).
A truncating and a missense MYBPC3 mutation were expressed in engineered heart tissue (EHT) from Mybpc3-KO mice.
KO EHTs displayed higher maximal force and sensitivity to external [Ca2+] than WT EHTs.
Haploinsufficiency affected EHT contractile function if WT cMyBP-C protein levels were ≤ 73%.
Missense or truncating mutation, but not WT did not fully restore the disease phenotype and had different pathogenic mechanisms, e.g. sarcomere poisoning for the missense mutation in KO EHTs.